The long-term objective of this program is to use melanopsin gene therapy to restore useful form vision and visual field to patients blind due to photoreceptor degeneration. Melanopsin is an invertebrate-like opsin present in rare, intrinsically-photosensitive, large-field ganglion cells of the mammalian retina not involved in the processing of spatial information. This pilot study is intended to demonstrate proof of principle with the following sequence of specific aims: (1) to express melanopsin in typical, small-field ganglion cells of mice with advanced photoreceptor degeneration, (2) to show that these modified ganglion cells have become intrinsically light-sensitive and to describe their stimulus-response characteristics, and (3) to show that melanopsin treatment improves the pattern discrimination of these mice. We will inject a recombinant adeno-associated virus (AAV) carrying the melanopsin gene and the GFP reporter gene (as a marker) into the vitreous of one eye of 1-month-old retinal degeneration (rd/rd) mice and use light microscopy to assess the level, extent, and persistence of transgene expression in ganglion cells. We will then use a microelectrode array on the retinal surface to record extracellular action potentials from ganglion cells of melanopsin-treated versus untreated eyes to demonstrate the photosensitivity and response characteristics of the transduced cells. We will then infer the visual acuity for melanopsin-treated versus untreated eyes by recording monocular pattern visually evoked potentials in response to an alternating stripe pattern of varying spatial frequency. If this pilot program is successful, then transfection of the melanopsin gene into typical, small-field ganglion cells of patients with hand-motions or worse vision and markedly constricted fields due to photoreceptor degeneration could be a future consideration to improve their visual acuity to ~20/100 and widen their visual field to enhance mobility. Restoration of useful form vision to some 4,000 such patients in the United States would facilitate their functioning independently in society and improve the long-term outlook of approximately 100,000 patients with generalized photoreceptor degeneration in this country who have not yet become blind. [unreadable] [unreadable]